Prostate cancer is the most common non-cutaneous cancer in American men. In May of 2012, the U.S. Preventive Task Force recommended that serum prostate specific antigen (PSA) screening no longer be recommended as standard clinical practice. A factor contributing to this recommendation is that many prostate cancers diagnosed via PSA-screening are indolent disease that will never progress. Current American Urologic Association recommendations stress informed decision making. To this end, this Clinical Validation Center will address the following major unmet clinical needs: 1) Optimize serum PSA screening protocols to identify men with aggressive diseases and reduce screening and detection of men with low risk disease (aim 1); 2) Validate markers that distinguish indolent versus aggressive disease using serum, DNA, urine, and tissue markers (aims 1 and 2); 3) Enhancing risk assessment for informed decision for individual patients, improving their ability to determine if a biopsy is in their best interest; 4) Develop a risk assessment tool for men on active surveillance to assist patients and physicians with decision making regarding biopsy. The SABOR EDRN Clinical Validation Center, established in 2000, has a long history of development of new tests for prostate cancer and critically evaluating such tests to ensure that, if they are used in the clinic, patients benefit from their use. Using the 4000-man SABOR cohort with other established cohorts (e.g., SWOG PCPT and PASS), Phase II and III validation studies will be conducted to improve biomarker performance related to prostate cancer risk and long term disease outcomes. The first aim focuses on assessing long term performance of current biomarkers including PHI, PCA3 and TMPRSS2:ERG. Also proposed in this aim are validation studies of constitutional genetic variants that may identify men at greater cancer risk or who are more likely to have poor disease outcomes. In aim 2, tissue microarrays (TMAs) will be developed for validating published markers of prognosis. In addition, TMAs that allow evaluation of performance of new tissue-based markers in ethnical/racial diverse tumors will be constructed. For the third aim, the PCPT risk calculator will be refined and a new tool developed to help men on active surveillance determine if a surveillance biopsy is necessary. The Center will continue its work to provide carefully-collected samples from patients to other investigators to either help discover the tests of the future or to conduct studies to ensure that the tests trul help patients. In addition, the SABOR scientific personnel will continue to provide service in leadership positions of the EDRN to ensure that the entire Network accelerates toward the goal of successful early detection and cure of cancer.